TY - JOUR
T1 - Rituximab or cyclosporine in the treatment of membranous nephropathy
AU - Fervenza, Fernando C.
AU - Appel, Gerald B.
AU - Barbour, Sean J.
AU - Rovin, Brad H.
AU - Lafayette, Richard A.
AU - Aslam, Nabeel
AU - Jefferson, Jonathan A.
AU - Gipson, Patrick E.
AU - Rizk, Dana V.
AU - Sedor, John R.
AU - Simon, James F.
AU - Mccarthy, Ellen T.
AU - Brenchley, Paul
AU - Sethi, Sanjeev
AU - Avila-casado, Carmen
AU - Beanlands, Heather
AU - Lieske, John C.
AU - Philibert, David
AU - Li, Tingting
AU - Thomas, Lesley F.
AU - Green, Dolly F.
AU - Juncos, Luis A.
AU - Beara-lasic, Lada
AU - Blumenthal, Samuel S.
AU - Sussman, Amy N.
AU - Erickson, Stephen B.
AU - Hladunewich, Michelle
AU - Canetta, Pietro A.
AU - Hebert, Lee A.
AU - Leung, Nelson
AU - Radhakrishnan, Jay
AU - Reich, Heather N.
AU - Parikh, Samir V.
AU - Gipson, Debbie S.
AU - Lee, Dominic K.
AU - Da Costa, Bruno R.
AU - Jüni, Peter
AU - Cattran, Daniel C.
N1 - Funding Information:
This investigator-initiated, open-label, randomized, multicenter, noninferiority trial was conducted at 22 sites in North America. As described previously,25 the trial was designed by the principal investigators and supported by Genentech and the Fulk Family Foundation. Genentech also donated rituximab; cyclosporine was purchased at the usual market price. The funders had no role in the trial design or conduct; the collection, management, analysis, or interpretation of the data; or in the preparation or review of the manuscript or the approval of the manuscript for submission. An independent data and safety monitoring board oversaw the trial (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Appropriately authorized ethics committees approved the trial at all participating sites. The manuscript was drafted and written by the first and last authors, with input as appropriate from the statistical team and the investigators. The authors collected the data and vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol (available at NEJM.org). The decision to submit the manuscript for publication was made by the authors.
Funding Information:
Supported by Genentech and the Fulk Family Foundation. Dr. Fervenza has received unrestricted research grants from Genen-tech, and Dr. Jüni is a Tier 1 Canada Research Chair in Clinical Epidemiology of Chronic Diseases, Canadian Institutes of Health Research.
PY - 2019/7/4
Y1 - 2019/7/4
N2 - BACKGROUND B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensinsystem blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI],-9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.)
AB - BACKGROUND B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensinsystem blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI],-9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.)
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U2 - 10.1056/NEJMoa1814427
DO - 10.1056/NEJMoa1814427
M3 - Article
C2 - 31269364
AN - SCOPUS:85068552015
VL - 381
SP - 36
EP - 46
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 1533-4406
IS - 1
ER -